Pharmacokinetics of a slower clearing tissue plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction.

The rapid clearance of t-PA from plasma requires administration by intravenous (I.V.) infusion. A slower clearing, fibrin-specific rt-PA variant may allow single intravenous bolus administration, thereby simplifying dosing. This study was designed to characterize the pharmacokinetics of the slower clearing, fibrin-specific tissue-plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction (AMI) following a single I.V. bolus injection. Single I.V. bolus doses of 5 to 50 mg of TNK-tPA were studied in an open-label, multicenter, dose escalation study. A total of 113 AMI patients were enrolled. Blood sampling for pharmacokinetics was conducted in eighty-two patients (72 men, 10 women), with 5 to 27 patients per dose. TNK-tPA was administered as an I.V. bolus over 5-10 s. Following I.V. bolus administration, there was a biphasic elimination of TNK-tPA from plasma. The initial phase had a mean half-life that ranged from 11 +/- 5 to 20 +/- 6 min and was followed by a terminal phase with a mean half-life that ranged from 41 +/- 16 to 138 +/- 84 min. Mean TNK-tPA plasma clearance was 125 +/- 25 - 216 +/- 98 ml/min, and the initial volume of distribution was 4.3 +/- 2 - 8.4 +/- 6 1. A decrease in TNK-tPA plasma clearance with increasing TNK-tPA dose was noted. In addition, women and patients with lower body weight or older age had a slower plasma clearance. In conclusion, TNK-tPA has a slower plasma clearance in patients with AMI than that reported for rt-PA, allowing administration as a single I.V. bolus.